A kinase-independent function of cyclin-dependent kinase 6 promotes outer radial glia expansion and neocortical folding
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ABSTRACT:
PROVIDER: PRJNA873102 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR21195526_1.fastq.gz | Fastqsanger.gz | |||
| SRR21195526_2.fastq.gz | Fastqsanger.gz | |||
| SRR21195527_1.fastq.gz | Fastqsanger.gz | |||
| SRR21195527_2.fastq.gz | Fastqsanger.gz | |||
| SRR21195528_1.fastq.gz | Fastqsanger.gz |
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Similar Datasets
Project description:The neocortex, the center for higher brain function, first emerged in mammals and has become massively expanded and folded in humans, constituting almost half the volume of the human brain. Primary microcephaly, a developmental disorder in which the brain is smaller than normal at birth, mainly results from there being fewer neurons in the neocortex because of defects in neural progenitor cells (NPCs). Outer radial glia (oRGs), NPCs that are abundant in gyrencephalic species but rare in lisencephalic species, are thought to play key roles in the expansion and folding of the neocortex. However, how oRGs expand, whether they are necessary for neocortical folding, and whether defects in oRGs cause microcephaly remain important questions in the study of brain development, evolution, and disease. Here, we show that oRG expansion in mice, ferrets, and human cerebral organoids requires cyclin-dependent kinase 6 (CDK6), the mutation of which causes primary microcephaly via an unknown mechanism. In a mouse model in which increased Hedgehog signaling expands oRGs and intermediate progenitor cells and induces neocortical folding, CDK6 loss selectively decreased oRGs and abolished neocortical folding. Remarkably, this function of CDK6 in oRG expansion did not require its kinase activity, was not shared by the highly similar CDK4 and CDK2, and was disrupted by the mutation causing microcephaly. Therefore, our results indicate that CDK6 is conserved to promote oRG expansion; that oRGs are necessary for neocortical folding; and that defects in oRG expansion may cause primary microcephaly.
2022-08-31 | GSE211990 | GEO
Project description:The neocortex, the center for higher brain function, first emerged in mammals and has become massively expanded and folded in humans, constituting almost half the volume of the human brain. Primary microcephaly, a developmental disorder in which the brain is smaller than normal at birth, results mainly from there being fewer neurons in the neocortex because of defects in neural progenitor cells (NPCs). Outer radial glia (oRGs), NPCs that are abundant in gyrencephalic species but rare in lissencephalic species, are thought to play key roles in the expansion and folding of the neocortex. However, how oRGs expand, whether they are necessary for neocortical folding, and whether defects in oRGs cause microcephaly remain important questions in the study of brain development, evolution, and disease. Here, we show that oRG expansion in mice, ferrets, and human cerebral organoids requires cyclin-dependent kinase 6 (CDK6), the mutation of which causes primary microcephaly via an unknown mechanism. In a mouse model in which increased Hedgehog signaling expands oRGs and intermediate progenitor cells and induces neocortical folding, CDK6 loss selectively decreased oRGs and abolished neocortical folding. Remarkably, this function of CDK6 in oRG expansion did not require its kinase activity, was not shared by the highly similar CDK4 and CDK2, and was disrupted by the mutation causing microcephaly. Therefore, our results indicate that CDK6 is conserved to promote oRG expansion, that oRGs are necessary for neocortical folding, and that defects in oRG expansion may cause primary microcephaly.
| S-EPMC9499540 | biostudies-literature
Project description:Evolution of the mammalian brain encompassed a remarkable increase in size of cerebral cortex, including tangential and radial expansion, but the mechanisms underlying these key parameters are still largely unknown. Here, we identified the novel DNA associated protein TRNP1 as a regulator of cerebral cortical expansion in both these dimensions. Gain and loss of function experiments in the mouse cerebral cortex in vivo demonstrate that high Trnp1 levels promote neural stem cell self-renewal and tangential expansion, while lower levels promote radial expansion resulting in a potent increase in the generation of intermediate progenitors and outer radial glial cells resulting in folding of the otherwise smooth murine cerebral cortex. Remarkably, TRNP1 expression levels exhibit regional differences also in the cerebral cortex of human fetuses anticipating radial or tangential expansion respectively. Thus, the dynamic regulation of TRNP1 is critical to regulate tangential and radial expansion of the cerebral cortex in mammals. We performed gene expression microarray analysis on embryonic mouse cerebral cortex derived from Trnp1 knockdown and control animals.
2013-04-26 | E-GEOD-40582 | biostudies-arrayexpress
Project description:Cell type composition and circuit organization of neocortical radial clones
| PRJNA591575 | ENA
Project description:Evolution of the mammalian brain encompassed a remarkable increase in size of cerebral cortex, including tangential and radial expansion, but the mechanisms underlying these key parameters are still largely unknown. Here, we identified the novel DNA associated protein TRNP1 as a regulator of cerebral cortical expansion in both these dimensions. Gain and loss of function experiments in the mouse cerebral cortex in vivo demonstrate that high Trnp1 levels promote neural stem cell self-renewal and tangential expansion, while lower levels promote radial expansion resulting in a potent increase in the generation of intermediate progenitors and outer radial glial cells resulting in folding of the otherwise smooth murine cerebral cortex. Remarkably, TRNP1 expression levels exhibit regional differences also in the cerebral cortex of human fetuses anticipating radial or tangential expansion respectively. Thus, the dynamic regulation of TRNP1 is critical to regulate tangential and radial expansion of the cerebral cortex in mammals.
2013-04-26 | GSE40582 | GEO
Project description:Excitatory neurons arising from a common progenitor establish radially-oriented clonal units in the neocortex which have been proposed to serve as elementary information processing modules. To characterize the cell types and circuit diagram within these clonal units, we performed single-cell RNA-sequencing and multi-cell patch clamp recordings of neurons derived from Nestin-positive progenitors. We found that radial clones do not appear to be fate-restricted, but instead individual clones are composed of a random sampling of the transcriptomic cell types present in a particular cortical area. The effect of lineage on synaptic connectivity depends on the type of connection tested: pairs of clonally related neurons were more likely to be connected vertically, across cortical layers, but not laterally within the same layer, compared to unrelated pairs. We propose that integration of vertical input from related neurons with lateral input from unrelated neurons may represent a developmentally programmed motif for assembling neocortical circuits.
2020-03-05 | GSE140946 | GEO
Project description:A massively expanded outer subventricular zone (OSVZ) in the primate and human has been proposed for generating majority of neocortical neurons, which consists of basally located radial glia cells. Previous studies with various strategies have tried to recognize genes specifically expressed in those cells; however, the molecular and cellular features of these cells still remain uncertain. By profiling gene expression across single cells isolated from cellular anatomy location and subtype sorting, we identified a primate-specific gene TMEM14B as a novel marker for basally located radial glia. Expression of TMEM14B induced dramatic increase in the number of radial glial and OSVZ region. Finally, we found that OSVZ progenitor’s extensive proliferative potential was up regulated through IQGAP1 phosphorylation and nuclear translocation, and remarkably, led to the gyrification in postnatal mouse. These results highlight that evolutionary expansion promoted by primate-specific genes enabling the evolutionary expansion and folding of the human neocortex.
2016-12-02 | GSE90734 | GEO
Project description:Cerebral organoids exhibit broad regional heterogeneity accompanied by limited cortical cellular diversity under a variety of derivation methods, suggesting inadequate patterning of early neural stem cell (NSC) starting populations. Here we show that a short combined Dual SMAD/WNT inhibition course during early organoid establishment is sufficient for yielding robust and lasting cortical identity with efficient suppression of non-cortical fates in organoid NSCs. In contrast, other widely used methods are inconsistent in their cortical specification capacity. Furthermore, combined inhibition selectively enriches for outer radial glia (oRG) cells in organoids that demarcate well-defined outer sub-ventricular (oSVZ)-like regions. Finally, combined inhibition enables superior NSC radial organization, further facilitates the generation of molecularly distinct deep and upper cortical layer neurons, and uncovers cortex-specific microcephaly defects. Thus, combined inhibition is critical for establishing a rich cortical cell repertoire, for enabling fundamental cytoarchitectural features of cortical development, and for meaningful disease modeling.
2022-03-16 | GSE189981 | GEO
Project description:The human neocortex is created from diverse progenitors that are intermixed with multiple cell types in the prenatal germinal zones. These progenitors have been difficult to profile with unbiased transcriptomics since progenitors-particularly radial glia (RG)-are rare cell types, defined by a combination of intracellular markers, position and morphology. To circumvent these problems, we developed a method called FRSCR for transcriptome profiling of individual fixed, stained, and sorted cells. After validation of FRSCR with human embryonic stem cells, we profiled primary human RG that constitute only 1% of the mid-gestation cortex. These data showed that RG could be classified into ventricle zone-enriched RG (vRG) that expressed ANXA1 and CRYAB, and outer subventricular zone-localized RG (oRG) that expressed HOPX. Our study identified the first markers and molecular profiles of vRG and oRG cells, and provides an essential step for understanding molecular networks that control the development and lineage of human neocortical progenitors. Furthermore, FRSCR allows targeted single-cell transcriptomic profiling of many tissues that currently lack live-cell markers.
2015-10-02 | GSE71858 | GEO
Project description:<p>The human neocortex is created from diverse intermixed progenitors in the prenatal germinal zones. These progenitors have been difficult to characterize since progenitors - particularly radial glia (RG) - are rare, and are defined by a combination of intracellular markers, position and morphology. To circumvent these problems we developed a method called FRISCR (Fixed and Recovered Intact Single Cell RNA) for transcriptome profiling of individual fixed, stained and sorted cells. We developed and validated FRISCR on human embryonic stem cells. We then profiled primary human RG (96 - 132 days post conception) that constitute only 1% of the mid-gestation cortex. These RG could be classified into ventricular zone-enriched RG (vRG) that express ANXA1 and CRYAB, and outer subventricular zone-localized RG (oRG) that express HOPX. Our study identifies the first markers and molecular profiles of vRG and oRG cells, and provides an essential step for understanding molecular networks driving the lineage of human neocortical progenitors.</p> <p><i>Reprinted from Thomsen et. al. Nature Methods (2015), with permission from Nature Publishing.</i></p> <p>Human embryonic stem cell data may be obtained through NCBI's GEO database, using accession number <a href="http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE71858">GSE71858</a>. Raw data from one human sample that was not consented to be released to dbGaP may be obtained directly from the authors of Thomsen et. al., 2015.</p>
| phs001016 | dbGaP